A team of virologists found potential targets for COVID-19 treatment. The targets could be inhibited to disrupt SARS-CoV-2 replication.
The potential targets for COVID-19 treatments were unveiled by virologists at Kansas State University (K-State), a public research university in the US. The targets called 3CLpro were confirmed crucial in viral replication. Small molecules were tested and found effective in inhibiting those targets. The effectiveness of the molecules was determined in MERS-CoV and SARS-CoV-2 coronaviruses. They published their findings in the journal Science Translational Medicine.
The 196th Situation Report on COVID-19
The race for the first approved COVID-19 vaccine is on. While confirming an approved vaccine is good news, the journey to a COVID-free world is still far from over. There are several factors that can affect the production and distribution of that vaccine. Moreover, the first vaccine is likely exclusive to adults since its components are yet to be tested in infants and children. A variant of that vaccine must be assessed for pediatric clinical trials, which are known for strict ethical rules.
According to the 196th Situation Report of the World Health Organization (WHO) of the United Nations, the total global confirmed cases of COVID-19 peaked at 17,918,582, as of August 3, 2020. While the total global confirmed deaths due to the disease peaked at 686,703, as of the same date. By region, the Americas remained with the highest confirmed cases at 9,630,598 and confirmed deaths at 363,162. It was followed by Europe with 3,391,779 confirmed cases and 213,559 confirmed deaths.
Southeast Asia reported 2,187,015 confirmed cases and 46,675 confirmed deaths. The Eastern Mediterranean confirmed 1,564,836 cases and 40,782 deaths. Africa confirmed 815,996 cases and 14,062 deaths. And finally, the Western Pacific reported 327,617 cases and 8,450 deaths. The WHO highlighted two ongoing actions in two countries for COVID-19.
Salah Alshaoof, a nutrition and health professional at a therapeutic feeding center in Yemen, reported the increased risk of children to COVID-19 due to malnutrition. As such, the organization supported 90 therapeutic feeding centers in the country to mitigate malnutrition among children. In Rwanda, robots joined the battle against the pandemic. Five human-sized robots acquired through a partnership were launched in May 2020. The machines were designed to significantly quicken COVID-19 screenings, such as body temperature checks and detection of vitals.
The ongoing surge in cases calls for a vaccine or effective treatments. Although certain vaccines have reached Phase III clinical trials, research must continue to address possible outcomes. One outcome is that vaccines may not completely neutralize the virus. Vaccinated people are less likely to experience severe symptoms and likely to recover faster. That outcome notifies the need for COVID-19 antivirals specifically designed for severe and critical cases.
Potential Targets for COVID-19 Antivirals
Firms like AstraZeneca, Pfizer, and Sinopharm successfully reached Phase III clinical trials. Their vaccines are centered around antibody activity in people. These experimental vaccines induce immune response to prepare the body for the real infection. Other vaccine models expected to be tested late this year or early next year are targeting further aspects of immunity. At K-State, virologists showed potential targets for future COVID-19 antivirals.
"Vaccine developments and treatments are the biggest targets in COVID-19 research, and treatment is really key. This paper describes protease inhibitors targeting coronavirus 3CLpro, which is a well-known therapeutic target," said Kyeong-Ok Chang, an author of the study and K-State's professor of diagnostic medicine and pathobiology.
In the study, the team examined the distinct mechanisms in three human pathogenic coronaviruses: the MERS-CoV, SARS-CoV, and SARS-CoV-2. Their attention has been focused on the replication process of these viruses. Their examination unveiled a common enzyme in all three coronaviruses – the 3C-like protease or 3CLpro. The absence of the enzyme would prevent the virus to replicate properly. Inhibitors against it could lead to treatments.
After uncovering the weakness, virologists looked into molecules that would affect the proteases. Via fluorescence resonance energy transfer enzyme assay and cell-based assays of Huh-7 and Vero E6 cell lines, the team tested those molecules and isolated the ones with inhibitory properties. Two molecules exhibited excellent inhibitory properties against 3CLpro.
In a biosafety level 3 lab, the team tested these molecules in cultured primary airway epithelial cells with SARS-CoV-2, and mice models infected with MERS-CoV. Results suggested the activity against both viruses, restricting respective replication processes. The details from an animal model showed increased survivability from 0% to 100%. The viral load of MERS-CoV also dropped substantially in that mouse, compared to other mice treated with different molecules. They concluded that the molecules could be developed further to formulate antivirals against SARS-CoV-2 and other human coronaviruses.
Virologists mentioned that the inhibitors were optimized for MERS-CoV and SARS-CoV-2. The optimization indicated extensive future research to properly develop human antivirals. If used in COVID-19 antiviral research, the inhibitors must be assessed for in-human safety. The lab experiments they conducted only involved cultured cells with SARS-CoV-2. The molecules could act differently in tissues and organs.
As of present, no therapeutic methods involving small molecules are approved for illnesses caused by MERS-CoV, SARS-CoV, and SARS-CoV-2. The only drug that demonstrated potential in the clinical setting has been remdesivir, recognized for its broad-spectrum antiviral activity. Unfortunately, the standard administration route of remdesivir comes with a risk of systemic reactions.
According to the National Institutes of Health of the US, remdesivir is an intravenous antiviral and remains an investigational treatment for COVID-19. Its application in COVID-19 is recommended among critically-ill patients who are receiving supplemental oxygen or mechanical ventilation. There is no sufficient evidence that remdesivir can improve the symptoms of mild or moderate COVID-19 patients.
Also, the drug must be given for five days or until hospital discharge, whichever comes first. If the patient did not show clinical improvement, some experts suggest extending remdesivir use for up to 10 days. Its safety for pregnant women and children is not yet evaluated. There is a possible risk of harm in the fetus and children, but under the US FDA Emergency Use Authorization, the drug may be administered to COVID-19 pediatric patients.
The two compounds are exclusively licensed to a pharmaceutical company, which is developing both for COVID-19.